Abstract
Dysbindin-1 regulates D2-receptor trafficking and is implicated in schizophrenia and related cognitive abnormalities, but whether this molecular effect mediates the clinical manifestations of the disorder is unknown. We explored in dysbindin-1-deficient mice (dys-/-) (1) schizophrenia-related behaviors, (2) molecular and electrophysiological changes in medial prefrontal cortex (mPFC) and (3) the dependence of these on D2-receptor stimulation. Dysbindin-1 disruption altered dopamine-related behaviors and impaired working memory under challenging/stressful conditions. Dys-/- pyramidal neurons in mPFC layers II/III were hyperexcitable at baseline but hypoexcitable following D2 stimulation. Dys-/- were also respectively more and less sensitive to D2 agonist- and antagonist-induced behavioral effects. Dys-/- had reduced expression of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and CaMKKβ in mPFC. Chronic D2 agonist treatment reproduced these changes in protein expression, and some of the dys-/- behavioral effects. These results elucidate dysbindin's modulation of D2-related behavior, cortical activity and mPFC CaMK components, implicating cellular and molecular mechanisms of the association of dysbindin with psychosis.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Action Potentials / drug effects
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Action Potentials / genetics
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Amphetamine / adverse effects
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Animals
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
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Carrier Proteins / genetics*
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Disease Models, Animal
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Dopamine / metabolism*
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Dopamine Agents / pharmacology
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Dysbindin
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Dystrophin-Associated Proteins
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Enzymologic / genetics
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Hyperkinesis / drug therapy
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Hyperkinesis / etiology
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Hyperkinesis / genetics
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Maze Learning / drug effects
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Memory Disorders / drug therapy
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Memory Disorders / etiology
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Memory, Short-Term / drug effects
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Memory, Short-Term / physiology
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Mice
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Mice, Inbred DBA
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Mice, Knockout
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Motor Activity / drug effects
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Motor Activity / genetics
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Prefrontal Cortex / drug effects
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Prefrontal Cortex / pathology
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Prefrontal Cortex / physiopathology*
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Pyramidal Cells / drug effects
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Reaction Time / drug effects
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Reaction Time / genetics
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Receptors, Dopamine D2 / metabolism*
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Schizophrenia / complications
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Schizophrenia / pathology*
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Sensory Gating / drug effects
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Sensory Gating / genetics
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Stress, Psychological / physiopathology
Substances
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Carrier Proteins
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Dopamine Agents
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Dtnbp1 protein, mouse
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Dysbindin
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Dystrophin-Associated Proteins
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Receptors, Dopamine D2
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Amphetamine
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Dopamine